Inhibitors of histone deacetylases (HDAC) have been shown to modulate transcription and to induce cell growth arrest, differentiation and apoptosis. HDAC inhibitors also enhance the cytotoxic effects of therapeutic agents used in cancer treatment, including radiation and chemotherapeutic drugs (Marks, P. et al., Nat. Rev. Cancer, 1, 194-202, (2001); and Marks, P. et al., Adv. Cancer Res, 91, 137-168, (2004)). Moreover, recent evidence indicates that transcriptional dysregulation may contribute to the molecular pathogenesis of certain neurodegenerative disorders, such as Huntington's disease, spinal muscular atrophy, amyotropic lateral sclerosis, and ischemia. (Langley, B. et al., Curr. Drug Targets CNS Neurol. Disord., 4, 41-50, (2005)). A recent review has summarized the evidence that aberrant histone acetyltransferase (HAT) and histone deacetylases (HDAC) activity may represent a common underlying mechanism contributing to neurodegeneration. HDAC activity has also been reported to contribute to long-term memory formation (Alarcon, Neuron, 42, 947-959, 2004). Moreover, using a mouse model of depression, Nestler has recently highlighted the therapeutic potential of histone deacetylation inhibitors (HDAC5) in depression (Tsankova, N. M. et al., Nat. Neurosci., 9, 519-525, (2006)). HDAC inhibition has been reported as having an effect in a variety of metabolic disorders (Pipalia, et al., PNAS, early release, approved Feb. 24, 2011; Li, et al., Diabetes, 61, 797-806 (2012); Lu, et al., PNAS, 108, 21200-21205 (2011)). The inhibition of HDAC3 has been shown to protect beta cells from cytokine-induced apoptosis (Chou, D H, et al. Chemistry & biology 19, 669-673 (2012)). Histone deacetylases 1 and 3 but not 2 have been shown to mediate cytokine-induced beta cell apoptosis in INS-1 cells and dispersed primary islets from rats and are differentially regulated in the islets of type 1 diabetic children (Lundh, M, et al., Diabetologia 55, 2421-2431 (2012)). The inhibition of HDAC3 has also been reported as having a role in activating latent HIV-1 (Huber, et al., J. Bio. Chem. 286, 25, 22211-22218 (2011)).
There are 18 known human histone deacetylases, grouped into four classes based on the structure of their accessory domains. Class I includes HDAC1, HDAC2, HDAC3, and HDAC8 and has homology to yeast RPD3. HDAC4, HDAC5, HDAC7, and HDAC9 belong to class IIa and have homology to yeast HDA1. HDAC6 and HDAC10 contain two catalytic sites and are classified as class IIb. Class III (the sirtuins) includes SIRT1, SIRT2, SIRT3, SIRT4, SIRT5, SIRT6, and SIRT7. HDAC11 is another recently identified member of the HDAC family and has conserved residues in its catalytic center that are shared by both class I and class II deacetylases and is sometimes placed in class IV.
There is still much to be understood about the family of HDACs, including the varying functions of different HDACs and the range of HDAC substrates. In order to learn more about the role that the individual HDACs play, it is important to develop compounds with binding selectivity for individual HDAC isoforms or for subsets of HDAC isoforms. While some degree of isoform selectivity has been shown by a few compounds, this problem of identifying selective inhibitors is far from solved, and the problem is complicated by the interactions of the HDACs with each other as well as other proteins (cofactors) that can possibly alter their interaction with various inhibitors (Glaser, et al., Biochem. Biophys. Res. Commun., 325, 683-690 (2004)).
Recent results indicate that HDAC3 is a critical negative regulator of long-term memory formation and may play a critical role in the molecular mechanisms underlying long-term memory formation. It has been demonstrated that knockout of HDAC3 in the brain of mice enhanced learning and memory and that administration of an HDAC3 selective compound (RGFP106) also enhanced learning and memory in mice (McQuown, S. C., et al., HDAC3 is a critical regulator of long-term memory formation. The Journal of Neuroscience, 31(1)(2011), 764-774)(see also, McQuown, Neurobiol. Learn. Mem. 2011, 96(1): 27-34 and WO 2012/016081). Despite the clinical efficacy of HDAC inhibitors, treatment of patients with HDAC inhibitors results in undesirable hematological side effects, such as anaemia and thrombocytopenia (loss of platelets). Side effects of HDAC inhibitors may be due to the targeting of (multiple) HDACs. For example, the dual knockdown of HDAC1 and 2 together has been shown to be involved in the mechanistic basis for thrombocytopenia (Wilting, R. H. et al., Overlapping functions of HDAC1 and HDAC2 in cell cycle regulation and haematopoiesis, EMBO Journal. (2010) 29, 1586-1597). The dose limiting toxicity of CI-994, a compound that inhibits HDAC1, HDAC2 and HDAC3, in humans is thrombocytopenia. It has also been shown that CI-994 is cytotoxic to megakaryocytes, the progenitor cell for platelets, presumably via inhibition of HDAC1 and HDAC2 (Volpe, D. A. et al, In vitro and in vivo effects of acetyldinaline on murine megakaryocytopoiesis. Cancer Chemother. Pharmacol. (2004) 54, 89-94).
HDAC inhibitors have great therapeutic potential. However, there is a need to identify specific and selective HDAC inhibitors e.g., selective HDAC3 inhibitors to identify the structural features required for potent HDAC inhibitory activity and define the relevant HDAC isoforms to target in specific disease indications. Clinically, the optimal dose, timing and duration of therapy, as well as the most appropriate agents to combine with HDAC inhibitors, are also still to be defined.